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1.
Axonal regeneration in the adult central nervous system (CNS) is limited by two proteins in myelin, Nogo and myelin-associated glycoprotein (MAG). The receptor for Nogo (NgR) has been identified as an axonal glycosyl-phosphatidyl-inositol (GPI)-anchored protein, whereas the MAG receptor has remained elusive. Here, we show that MAG binds directly, with high affinity, to NgR. Cleavage of GPI-linked proteins from axons protects growth cones from MAG-induced collapse, and dominant-negative NgR eliminates MAG inhibition of neurite outgrowth. MAG-resistant embryonic neurons are rendered MAG-sensitive by expression of NgR. MAG and Nogo-66 activate NgR independently and serve as redundant NgR ligands that may limit axonal regeneration after CNS injury. 相似文献
2.
Atwal JK Pinkston-Gosse J Syken J Stawicki S Wu Y Shatz C Tessier-Lavigne M 《Science (New York, N.Y.)》2008,322(5903):967-970
A major barrier to regenerating axons after injury in the mammalian central nervous system is an unfavorable milieu. Three proteins found in myelin--Nogo, MAG, and OMgp--inhibit axon regeneration in vitro and bind to the glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, genetic deletion of NgR has only a modest disinhibitory effect, suggesting that other binding receptors for these molecules probably exist. With the use of expression cloning, we have found that paired immunoglobulin-like receptor B (PirB), which has been implicated in nervous system plasticity, is a high-affinity receptor for Nogo, MAG, and OMgp. Interfering with PirB activity, either with antibodies or genetically, partially rescues neurite inhibition by Nogo66, MAG, OMgp, and myelin in cultured neurons. Blocking both PirB and NgR activities leads to near-complete release from myelin inhibition. Our results implicate PirB in mediating regeneration block, identify PirB as a potential target for axon regeneration therapies, and provide an explanation for the similar enhancements of visual system plasticity in PirB and NgR knockout mice. 相似文献
3.
McGee AW Yang Y Fischer QS Daw NW Strittmatter SM 《Science (New York, N.Y.)》2005,309(5744):2222-2226
Monocular deprivation normally alters ocular dominance in the visual cortex only during a postnatal critical period (20 to 32 days postnatal in mice). We find that mutations in the Nogo-66 receptor (NgR) affect cessation of ocular dominance plasticity. In NgR-/- mice, plasticity during the critical period is normal, but it continues abnormally such that ocular dominance at 45 or 120 days postnatal is subject to the same plasticity as at juvenile ages. Thus, physiological NgR signaling from myelin-derived Nogo, MAG, and OMgp consolidates the neural circuitry established during experience-dependent plasticity. After pathological trauma, similar NgR signaling limits functional recovery and axonal regeneration. 相似文献
4.
LeCouter J Moritz DR Li B Phillips GL Liang XH Gerber HP Hillan KJ Ferrara N 《Science (New York, N.Y.)》2003,299(5608):890-893
The vascular endothelium was once thought to function primarily in nutrient and oxygen delivery, but recent evidence suggests that it may play a broader role in tissue homeostasis. To explore the role of sinusoidal endothelial cells (LSECs) in the adult liver, we studied the effects of vascular endothelial growth factor (VEGF) receptor activation on mouse hepatocyte growth. Delivery of VEGF-A increased liver mass in mice but did not stimulate growth of hepatocytes in vitro, unless LSECs were also present in the culture. Hepatocyte growth factor (HGF) was identified as one of the LSEC-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGF receptor-1 (VEGFR-1) stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin. Thus, VEGFR-1 agonists may have therapeutic potential for preservation of organ function in certain liver disorders. 相似文献
5.
Takano K Watanabe-Takano H Suetsugu S Kurita S Tsujita K Kimura S Karatsu T Takenawa T Endo T 《Science (New York, N.Y.)》2010,330(6010):1536-1540
Insulin-like growth factor 1 (IGF-1) induces skeletal muscle maturation and enlargement (hypertrophy). These responses require protein synthesis and myofibril formation (myofibrillogenesis). However, the signaling mechanisms of myofibrillogenesis remain obscure. We found that IGF-1-induced phosphatidylinositol 3-kinase-Akt signaling formed a complex of nebulin and N-WASP at the Z bands of myofibrils by interfering with glycogen synthase kinase-3β in mice. Although N-WASP is known to be an activator of the Arp2/3 complex to form branched actin filaments, the nebulin-N-WASP complex caused actin nucleation for unbranched actin filament formation from the Z bands without the Arp2/3 complex. Furthermore, N-WASP was required for IGF-1-induced muscle hypertrophy. These findings present the mechanisms of IGF-1-induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation. 相似文献
6.
YIGSR, a synthetic laminin pentapeptide, inhibits experimental metastasis formation 总被引：30，自引：0，他引：30
Y Iwamoto F A Robey J Graf M Sasaki H K Kleinman Y Yamada G R Martin 《Science (New York, N.Y.)》1987,238(4830):1132-1134
The invasion of tumor cells through basement membranes is a critical step in the formation of metastases. The binding of the malignant cells to laminin in the basement membranes allows their attachment and activates their invasiveness. Recently a synthetic nonapeptide from the B1 chain sequence of laminin was identified as a major site for cell binding. A pentapeptide within the nonapeptide sequence was found to reduce the formation of lung colonies in mice injected with melanoma cells and also to inhibit the invasiveness of the cells in vitro. 相似文献
7.
Kim KA Kakitani M Zhao J Oshima T Tang T Binnerts M Liu Y Boyle B Park E Emtage P Funk WD Tomizuka K 《Science (New York, N.Y.)》2005,309(5738):1256-1259
Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection into mice, the protein induced rapid onset of crypt cell proliferation involving beta-catenin stabilization, possibly by a process that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced intestinal mucositis and may have therapeutic application in gastrointestinal diseases. 相似文献
8.
《东北农业大学学报(英文版)》2020,(2)
RanBP1 is a binding protein of Ran that plays a pivotal role in nucleocytoplasmic transport.In this study,the localization and possible functions of RanBP1 were examined,during the early embryonic development of mice.Immunofluorescence results showed that RanBP1 was mainly localized in cytoplasm at mitosis interphase,and its concentration was lower in nucleus and the lowest in nucleolus.With the formation of the spindle in the early embryonic cells,RanBP1 condensed area took the shape of spindle microtubule,the concentration of RanBP1 was low in the site of chromosome.During the formation of nucleus,RanBP1 concentrated in nucleus and there were few dots of RanBP1 around the nucleolus.These dots were lost after the nucleus full growth.The results showed that RanBP1 had important roles in nucleocytoplasmic transport,spindle formation and nuclear assembly in the early embryonic development of mice. 相似文献
9.
Cichowski K Shih TS Schmitt E Santiago S Reilly K McLaughlin ME Bronson RT Jacks T 《Science (New York, N.Y.)》1999,286(5447):2172-2176
Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome resulting from germ line mutations in the NF1 tumor suppressor gene. Hallmark features of the disease are the development of benign peripheral nerve sheath tumors (neurofibromas), which can progress to malignancy. Unlike humans, mice that are heterozygous for a mutation in Nf1 do not develop neurofibromas. However, as described here, chimeric mice composed in part of Nf1-/- cells do, which demonstrates that loss of the wild-type Nf1 allele is rate-limiting in tumor formation. In addition, mice that carry linked germ line mutations in Nf1 and p53 develop malignant peripheral nerve sheath tumors (MPNSTs), which supports a cooperative and causal role for p53 mutations in MPNST development. These two mouse models provide the means to address fundamental aspects of disease development and to test therapeutic strategies. 相似文献
10.
Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells 总被引：80，自引：0，他引：80
H J Huang J K Yee J Y Shew P L Chen R Bookstein T Friedmann E Y Lee W H Lee 《Science (New York, N.Y.)》1988,242(4885):1563-1566
Mutational inactivation of the retinoblastoma susceptibility (RB) gene has been proposed as a crucial step in the formation of retinoblastoma and other types of human cancer. This hypothesis was tested by introducing, via retroviral-mediated gene transfer, a cloned RB gene into retinoblastoma or osteosarcoma cells that had inactivated endogenous RB genes. Expression of the exogenous RB gene affected cell morphology, growth rate, soft agar colony formation, and tumorigenicity in nude mice. This demonstration of suppression of the neoplastic phenotype by a single gene provides direct evidence for an essential role of the RB gene in tumorigenesis. 相似文献
11.
[目的]探讨饲料中添加复合益生菌对断奶小鼠的安全性及其肠道酶活性的影响。[方法]以蜡样芽孢杆菌B1-1、蜡样芽孢杆菌JC128和乳酸杆菌SL1-5制备复合益生菌剂。以复合益生菌饲喂昆明小鼠,评价其安全性,并分析其对断奶昆明小鼠生长性能、肠道纤维素酶活和蛋白酶活力的影响。[结果]此3株菌株制备的复合益生菌安全的较好,能显著提高昆明小鼠日增重。试验组的小鼠在饲喂含有复合益生菌制剂的添加剂后,其肠道内的蛋白酶活和纤维素酶活都明显高于对照组。[结论]复合益生菌能够显著提高昆明小鼠的生长性能和肠道内酶活力。 相似文献
12.
【目的】对初步鉴定的牛种布鲁氏菌分离株（B. abortus 343）进行全面的生物学特性检定,为深入研究布鲁氏菌病提供参考菌株。【方法】将B. abortus 343划线培养及梯度稀释,使其形成单个菌落,观察菌落形态。挑取单个菌落进行革兰氏染色和柯氏染色,观察其染色特点;分别接种1.5×106 CFU到含硫瑾（1﹕25 000）或含碱性复红（1﹕25 000）的TSA平板上,观察其生长状态;将接种有B. abortus 343的TSA平板分别置于普通培养箱和CO2培养箱37℃培养72 h,观察其对CO2的依赖性;通过醋酸铅试纸条测定B. abortus 343代谢过程中是否释放H2S。通过平板凝集试验测定布鲁氏菌单相特异性血清（ 牛种布鲁氏菌单因子血清A、羊种布鲁氏菌单因子血清M 和 布鲁氏菌粗糙型血清R ）与B. abortus 343抗原的反应性;利用布鲁氏菌AMOS-PCR种属分型等方法对B. abortus 343进行了PCR种属特性鉴定;将B. abortus 343免疫小鼠,分别测定其抗血清与光滑型和粗糙型抗原的反应性;通过小鼠和豚鼠感染试验,全面评价该分离株的毒力;分别以1×105 CFU感染6周龄Balb/c小鼠,测定B. abortus 343在小鼠体内存活时间;以1×109 CFU感染Hartley豚鼠,2周后测定试验豚鼠每克脾脏含菌量;分别以10 000、1 000、100、25 CFU/只4种不同剂量感染豚鼠,初步测定分离株对豚鼠的最小感染量（MID）,在此基础上,进一步以40、60和90 CFU/只测定MID。【结果】分离株B. abortus 343 为光滑型牛种布鲁氏菌,菌落逆光观察微带蓝绿色乳光;革兰氏染色为阴性,柯氏染色为红色,H2S试验阳性。该菌能在含硫瑾和碱性复红的培养基上生长,不依赖于CO2。B. abortus 343抗原能与A因子血清呈明显凝集反应,免疫小鼠后能产生特异性抗体。以1×105 CFU感染6周龄Balb/c小鼠,可在小鼠体内存活29周;以1×109 CFU感染350-400 g雌性豚鼠,14 d后豚鼠每克脾脏含菌量2.4×105-1.2×106;以1×105 CFU感染豚鼠1个月后,所有试验豚鼠均能产生特异性光滑型抗体,试管凝集效价为320-1 280;B. abortus 343对豚鼠的最小感染量约为40 CFU。【结论】鉴定了一株中等毒力牛种布鲁氏菌（B. abortus 343）,为深入研究布鲁氏菌病提供了参考菌株,丰富了布鲁氏菌菌种资源。 相似文献
13.
mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination 总被引：1，自引：0，他引：1
Ichise T Kano M Hashimoto K Yanagihara D Nakao K Shigemoto R Katsuki M Aiba A 《Science (New York, N.Y.)》2000,288(5472):1832-1835
Targeted deletion of metabotropic glutamate receptor-subtype 1 (mGluR1) gene can cause defects in development and function in the cerebellum. We introduced the mGluR1alpha transgene into mGluR1-null mutant [mGluR1 (-/-)] mice with a Purkinje cell (PC)-specific promoter. mGluR1-rescue mice showed normal cerebellar long-term depression and regression of multiple climbing fiber innervation, events significantly impaired in mGluR1 (-/-) mice. The impaired motor coordination was rescued by this transgene, in a dose-dependent manner. We propose that mGluR1 in PCs is a key molecule for normal synapse formation, synaptic plasticity, and motor control in the cerebellum. 相似文献
14.
Holm TM Habashi JP Doyle JJ Bedja D Chen Y van Erp C Lindsay ME Kim D Schoenhoff F Cohn RD Loeys BL Thomas CJ Patnaik S Marugan JJ Judge DP Dietz HC 《Science (New York, N.Y.)》2011,332(6027):358-361
Transforming growth factor-β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal-regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase-1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease. 相似文献
15.
The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice 总被引：77，自引：0，他引：77
M Nerenberg S H Hinrichs R K Reynolds G Khoury G Jay 《Science (New York, N.Y.)》1987,237(4820):1324-1329
Human T-lymphotropic virus type 1 (HTLV-1) is a suspected causative agent of adult T-cell leukemia. One of the viral genes encodes a protein (tat) that not only results in transactivation of viral gene expression but may also regulate the expression of certain cellular genes that are important for cell growth. Transgenic mice that expressed the authentic tat protein under the control of the HTLV-1 long terminal repeat were generated, and cell types that are permissive for the viral promoter and the effects of the tat gene on these cells were studied. Three of eight founder mice with high levels of expression of the transgene in muscle were bred and then analyzed. All developed soft tissue tumors at multiple sites between 13 to 17 weeks of age. This phenotype was transmitted to nine of nine offspring that inherited the tat gene and were available for analysis. The remaining five founders expressed the transgene in the thymus, as well as in muscle. This second group of mice all exhibited extensive thymic depletion and growth retardation; in all of these mice, death occurred between 3 to 6 weeks of age before tumors became macroscopically visible. The tat gene under the control of the HTLV-1 regulatory region showed tissue-specific expression and the tat protein efficiently induced mesenchymal tumors. The data establish tat as an oncogenic protein and HTLV-1 as a transforming virus. 相似文献
16.
企业知识管理解决方案软件平台选择的分析研究 总被引：1，自引：0，他引：1
随着知识管理理论和实践的不断深入,有关企业知识管理解决方案也在不断地出现。本文通过分析LO-TUS、微软以及清华同方三家公司提供的知识管理解决方案,找出知识管理解决方案的不同点与相同点,从而指出了企业如何根据自身的特点选择相应的知识管理解决方案。 相似文献
17.
Andries K Verhasselt P Guillemont J Göhlmann HW Neefs JM Winkler H Van Gestel J Timmerman P Zhu M Lee E Williams P de Chaffoy D Huitric E Hoffner S Cambau E Truffot-Pernot C Lounis N Jarlier V 《Science (New York, N.Y.)》2005,307(5707):223-227
The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase. 相似文献
18.
Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta 总被引：19，自引：0，他引：19
In Rous sarcoma virus (RSV)-infected chickens, wounding leads to tumor formation with nearly 100% frequency in tissues that would otherwise remain tumor-free. Identifying molecular mediators of this phenomenon should yield important clues to the mechanisms involved in RSV tumorigenesis. Immunohistochemical staining showed that TGF-beta is present locally shortly after wounding, but not unwounded controls. In addition, subcutaneous administration of recombinant transforming growth factor-beta 1 (TGF-beta 1) could substitute completely for wounding in tumor induction. A treatment protocol of four doses of 800 nanograms of TGF-beta resulted in v-src-expressing tumors with 100% frequency; four doses of only 10 nanograms still led to tumor formation in 80% of the animals. This effect was specific, as other growth factors with suggested roles in wound healing did not elicit the same response. Epidermal growth factor (EGF) or TGF-alpha had no effect, and platelet-derived growth factor (PDGF) or insulin-like growth factor-1 (IGF-1) yielded only occasional tumors after longer latency. TGF-beta release during the wound-healing response may thus be a critical event that creates a conducive environment for RSV tumorigenesis and may act as a cofactor for transformation in this system. 相似文献
19.
水溶性灵芝肽在动物体外的抗氧化活性 总被引：3，自引：0，他引：3
【目的】研究水溶性灵芝肽在动物体外的抗氧化活性。【方法】用丙二醛(MDA)试剂盒测定MDA含量，用分光光度法测定大鼠血清自氧化溶血及小鼠肝线粒体肿胀度。【结果】当水溶性灵芝肽的剂量为0.25 mg•ml-1时，对大鼠红细胞自氧化溶血的抑制率达62.33%，对溶血过程中MDA生成的抑制率达91.24%；在有或无自由基诱导剂（Fe2+或H2O2）时，0.35 mg•ml-1的水溶性灵芝肽均能极显著抑制小鼠肝匀浆中MDA的生成（P＜0.01），且抑制率大致相当，为60%左右；当水溶性灵芝肽剂量为1.00 mg•ml-1时，对线粒体肿胀度的抑制率为90.52%，对线粒体中MDA生成的抑制率达65.42%，且呈明显剂量-效应关系。【结论】水溶性灵芝肽在体外具有明显的抗氧化作用。 相似文献
20.
Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth 总被引：12，自引：0，他引：12
The hormone 17 beta-estradiol acts through its receptor system to induce MCF-7 human breast cancer cells to form tumors in athymic mice. In vitro studies have identified the production of estrogen-induced growth factors from MCF-7 cells that may have a role in growth control. These induced growth factors were sufficient to stimulate MCF-7 tumor growth in ovariectomized athymic mice, thus partially replacing estradiol. Growth factors may act as estrogen-induced "second messengers" in estrogen-responsive growth of human breast cancer. 相似文献